The present invention is generally directed to cardiac therapy, and more particularly to treating, preventing, or ameliorating heart failure and/or cardiac hypertrophy, and/or dysfunction by reactivating silenced adult cardiac gene expression.
Heart failure is a leading case of death and disability. Hospitalization and long-term care for this condition represent major health care costs items. Among other entities, hypertension is a major factor underlying the development of heart failure.
Neither the cause of hypertension or mechanisms underlying heart failure are fully understood. It is clear, however, that increased neurohormonal activity accompanies heart failure and ameliorating this activity by beta adrenergic antagonists and inhibitors of the rennin-angiotensin aldosterone system improves clinical state. These treatments represent cornerstones in the management of heart failure today.
Although symptomatic improvement in heart failure patients is found with neurohumoral blockade, reversal of the underlying pathophysiology does not take place. Pathological events include adverse remodeling of the myocardium, associated with a modification of gene expression, an increase in left ventricular mass, depression of intrinsic myocardial function.
Conventional treatments for heart failure are designed to stabilize disease progression and are primarily limited to the administration of an angiotensin converting enzyme (ACE) inhibitor, angiotensin receptor blocker, beta adrenergic blocker, or diuretic. For example, a ACE inhibitor, such as captopril, is frequently administered to patients with hypertension and acutely decompensated heart failure. The efficacy of ACE inhibitors, such as captopril, is based on their ability to reduce circulation levels of angiotensin 11, to thereby reduce mean arterial pressure and systemic vascular resistance. This results in decreased workload on the heart in patients with heart failure. This treatment may temporarily reduce clinical symptoms of heart failure, however, does not effectively treat the underlying disease and the long-term outlook for heart failure patients remains poor.
Much of the pathophysiology associated with heart failure may be due, in large part, to abnormal gene transcription that results from aberrant silencing of adult cardiac gene expression and recapitulation of the fetal gene program. Histone acetylase and deacetylaces can play a role in the control of gene expression. A prior patent document (US Patent Application Publication No. 2006/0025333) entitled “Inhibition of histone deacetylases as a treatment for cardiac hypertrophy” provides methods for treatment and prevention of cardiac hypertrophy in patients at risk of developing heart failure by administration of class II histone deacetylases (HDAC) inhibitors, consisting of tricoststin A, trapoxin B, MS 275-27, m-carboxycinnamic acid bis-hydroxamide, depudecin, oxamflatin, apicidin, suberoylanilide hydroxamic acid, Scriptaid, pyroxamide, 2-amino-8oxo-9,10-epoxy-decanoyl, 3-(4-aroyl-1H-pyrrol-2-yl)-N-hydroxy-2- -propenamide and FR901228. However, it is noted that this patent document does not include phenylbutyrate. Aside from the actions of HDACs, when DNA is methylated in the promotor region of genes, where transcription is initiated, normal adult genes are inactivated and silenced (Reference 1), which can lead to recapitulation of the fetal gene profile that characterizes the failing heart.
As noted above, angiotensin converting enzyme inhibitors, the primary standard treatment for hypertension and heart failure, are designed to stabilize disease progression. However, myocardial dysfunction involving depressed myocardial contractility and cardiac enlargement due, in large part, to pathologic gene expression remains unresolved. An approach to selectively target cardiac gene transcription to alter gene expression, and thereby restore the adult cardiac profile, reduce ventricular mass and increase contractile function is needed to effectively treat heart failure.
Histone deacetylase inhibitors are substances causing inhibition of the activity of histone deacetylase, resulting in hyperacetylation and leading to chromatin relaxation and wide scale changes of gene expression. Current compounds shown to inhibit the activity of histone deacetylases fall into six structurally diverse classes. Phenylbutyrate (MW 164.21), comprises the short chain fatty acid class and is well-tolerated clinically at drug concentrations, which effect acetylation of histones in vitro. Phenylbutyrate has been used for the treatment of urea cycle disorders in children, sickle cell disease, thalassemia, cancer and more recently for the treatment of cystic fibrosis and ALS disease. However, thus far, phenylbutyrate has not been used for the treatment of heart failure.